ORIGINAL RESEARCH ARTICLE
`
`Clin Drug Invest 2004; 24 (11): 633-639
`1173-2563/04/0011-0633/$31.00/0
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Bioavailability and Pharmacokinetics
`of Intranasal Hydromorphone
`in Patients Experiencing
`Vasomotor Rhinitis
`George A. Davis,1 Anita C. Rudy,2 Sanford M. Archer,3 Daniel P. Wermeling1 and
`Patrick J. McNamara1
`1 College of Pharmacy, University of Kentucky, Lexington, Kentucky, USA
`2 Intranasal Technology Inc., Lexington, Kentucky, USA
`3 College of Medicine, University of Kentucky, Lexington, Kentucky, USA
`
`Abstract
`
`Background and objective: Narcotic analgesics such as hydromorphone under-
`go an extensive first-pass effect resulting in a low systemic bioavailability
`following oral administration. Alternative dosing routes, such as rectal and
`intranasal (IN) routes, have been suggested as options for oral or intravenous
`administration. Rhinitis and pharmacological agents used for treatment are con-
`sidered factors that could alter the rate and extent of absorption of drugs adminis-
`tered by the nasal route. The purpose of this study was to evaluate the
`pharmacokinetics of intranasal hydromorphone hydrochloride (HCl) in patients
`with vasomotor rhinitis.
`Methods: Ten patients completed the randomised, three-way crossover study.
`During the three treatment periods, a single dose of hydromorphone HCl 2.0mg
`was administered via intravenous infusion (treatment A) and the intranasal route
`without (treatment B) or with (treatment C) vasoconstrictor pretreatment for
`rhinitis. Blood samples were collected serially from 0 to 16 hours. Noncompart-
`mental methods were used to determine pharmacokinetic parameters.
`Results: Maximum plasma concentrations were 3.69 and 3.38 µg/L for treatments
`B and C, respectively. Mean (% coefficient of variation) bioavailability of
`intranasal hydromorphone was 54.4% (34.8) and 59.8% (22.1) with and without
`pretreatment, respectively. Pretreatment of rhinitis did not significantly affect the
`rate or extent of absorption of hydromorphone in this study. There was not a
`significant difference in bioavailability between treated and untreated rhinitis.
`Conclusions: This study found intranasal administration of hydromorphone in
`patients experiencing vasomotor rhinitis had acceptable bioavailability and a
`pharmacokinetic profile comparable to previous studies. These data support
`further investigation of this single-dose delivery system for clinical use.
`
`Hydromorphone, a µ-selective opioid agonist, is
`a semisynthetic derivative of morphine used for the
`management of postoperative pain and moder-
`ate-to-severe chronic pain associated with terminal
`
`illnesses, such as cancer.[1-3] On a milligram basis,
`hydromorphone is 5–8.5 times as potent as mor-
`phine when given by the oral route, and 5–7.5 times
`as potent as morphine when given intravenously.[4]
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`AQUESTIVE EXHIBIT 1120 Page 0001
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`

`634
`
`Davis et al.
`
`Patients and Methods
`
`Narcotic analgesics such as hydromorphone and mental conditions such as cold air, high humidity,
`morphine have been suggested to undergo an exten-
`strong odours and inhaled irritants. Rhinitis, regard-
`sive first-pass effect resulting in a low systemic
`less of aetiology, is considered a factor that could
`bioavailability following oral administration. Simi-
`alter the rate and extent of absorption of drugs
`lar to morphine, hydromorphone has been reported
`administered by the nasal route. Moreover, it is also
`to have wide interindividual variation of oral bio-
`common for patients with rhinitis to use nasal vaso-
`availability ranging from 10% to 65%.[5-9]
`constrictors or oral decongestants as treatment.
`Treatment with these agents could theoretically alter
`Alternative dosing routes, such as rectal and in-
`the extent and rate of nasal absorption of other
`tranasal (IN), have been suggested as options for
`medications.
`oral or intravenous administration of opioids.[10]
`The objectives of this study were to assess the
`Rectal administration of hydromorphone has been
`absolute bioavailability and single-dose tolerance of
`evaluated in healthy adults and found to have low
`intranasal hydromorphone hydrochloride (HCl), and
`bioavailability (33%) with wide interindividual vari-
`the effect of an oral decongestant (pseudoephedrine)
`ation (10–65%).[6,7] Factors potentially influencing
`or nasal vasoconstrictor (oxymetazoline) on the rate
`rectal bioavailability include poor absorption from
`or extent of absorption of IN hydromorphone in
`the rectal mucosa because of high ionisation, small
`patients experiencing vasomotor rhinitis.
`rectal surface area, slow release from the supposito-
`ry, reduced contact with the rectal epithelial tissue,
`and first-pass elimination.[6]
`The IN route potentially improves systemic bio-
`availability of drugs since it bypasses gastrointesti-
`nal degradation and the hepatic first-pass effect.
`Potential advantages of IN administration include
`Twelve nonsmoking patients with vasomotor rhi-
`ease of administration, rapid onset and patient con-
`nitis (five males, seven females) between the ages of
`trol. There are also potential benefits in safety with
`28 and 55 years participated in this inpatient study
`the avoidance of needles associated with intrave-
`after providing written informed consent. The
`nous (IV) or intramuscular (IM) administration. An Medical Institutional Review Board of the Univer-
`alternative dosing route may also be valuable in
`sity of Kentucky approved the study.
`patients experiencing nausea and vomiting or in the
`Study participants were selected based on
`paediatric setting. Other narcotics, such as al- medical history, physical and nasal examinations,
`fentanil, butorphanol, buprenorphine, fentanyl, oxy-
`vital signs, clinical laboratory tests and their history
`codone and sufentanil, have been evaluated in
`of nonallergic rhinitis. An allergy questionnaire was
`humans following intranasal administration with fa-
`used by an otolaryngologist to screen patients to
`vourable results.[9]
`distinguish between allergic and nonallergic rhinitis.
`Rhinitis, inflammation of the nasal mucosa, is a
`Patients had no acute or chronic nasal symptoms
`common condition in which the permeability of the
`other than the nonallergic rhinitis, and no clinically
`nasal mucosa increases, nasal blood flow increases,
`significant previous nasal surgery or polyps or other
`and secretions permeate out of the nasal glands.[10]
`physical abnormalities of the nose, cardiovascular,
`Chronic rhinitis is classified by aetiology as allergic
`gastrointestinal,
`renal, hepatic, pulmonary or
`or nonallergic. Allergic rhinitis is the most prevalent
`haematological disease. Patients abstained from al-
`type of chronic rhinitis, but 30–50% of patients
`cohol and caffeine-containing beverages 48 hours
`diagnosed with rhinitis may have nonallergic
`before the dosing period and during the study. Pa-
`causes.[11] Vasomotor rhinitis is a subtype of nonal-
`tients were asked to abstain from prescription and
`lergic rhinitis and described as chronic, noninfec-
`nonprescription drugs that might interact with
`tious rhinitis usually without nasal eosinophilia.
`hydromorphone metabolism or nasal physiology,
`Vasomotor rhinitis manifests as nasal symptoms with the exception of pseudoephedrine and ox-
`(rhinorrhoea, nasal congestion, sneezing and
`ymetazoline provided for this study. Patients receiv-
`postnasal drip) that occur in response to environ-
`ing the IV dose were allowed to take their usual
`
`Subjects
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
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`Pharmacokinetics of Intranasal Hydromorphone
`
`635
`
`rhinitis medications as approved by the medical
`supervisor.
`
`and the plasma was transferred to polypropylene
`tubes and stored at approximately –20°C.
`
`Study Procedures
`
`Dose Administration
`
`For treatment A, hydromorphone HCl 2.0mg (Di-
`laudid® Injection, 1 mg/mL) was diluted to 10mL
`and infused over 10 minutes. IN doses (treatments B
`and C) of hydromorphone HCl were administered
`using a single-dose spray pump (Pfeiffer of
`America, Princeton, NJ, USA). Patients were asked
`to gently blow their nose immediately prior to in-
`tranasal administration and were then not allowed to
`blow their nose again until 60 minutes following
`drug administration. A single spray of hydromor-
`phone HCl (1.0mg/100µL) was administered to the
`lateral nasal wall of each nostril. Patients remained
`in bed at a 30- to 45-degree angle prior to and for 2
`hours following drug administration.
`
`This was a randomised, three-way crossover, sin-
`gle-dose study with each treatment separated by a
`washout period of at least 2 days. Twelve patients
`were enrolled and randomised to one of six se-
`quence groups (ABC, ACB, BCA, BAC, CAB or
`CBA) to receive each of the following treatments:
`Treatment A: IV hydromorphone HCl 2.0mg
`Treatment B: IN hydromorphone HCl 2.0mg
`Treatment C: IN hydromorphone HCl 2.0mg
`with pretreatment for rhinitis.
`In a random manner, half of the subjects received
`vasoconstrictor pretreatment consisting of a
`60mg oral dose of pseudoephedrine hydrochloride
`(Sudafed®, Pfizer Inc., New York, NY, USA)1 ad-
`ministered 1 hour before or two nasal sprays per
`nostril of 0.05% oxymetazoline (Afrin®, Schering-
`Plough, Kenilworth, NJ, USA) administered im-
`mediately prior to dosing.
`Eleven patients reported to the research centre
`the night prior to treatment and one patient was
`admitted the morning of the treatment, 2 hours prior
`to dosing. Study patients remained in the centre
`approximately 16 hours after dosing. Drug adminis-
`tration occurred at approximately 8am on each study
`day. Except for water ad libitum, the study patients
`underwent an overnight fast of ≥8 hours. Blood
`pressure, respiration and pulse rate were measured
`at predetermined times throughout the study. Ad-
`verse events were monitored by study personnel.
`Nasal examinations were completed by an oto-
`Pharmacokinetic parameters were determined us-
`laryngologist prior to study drug administration, 2–4
`ing standard noncompartmental methods with log-
`hours after administration, and at the post-study
`linear least square regression analysis to determine
`evaluation. Any significant change in nasal physiol-
`the elimination rate constants using WinNonlin
`ogy was documented as an adverse effect and rela-
`(version 3.2, Pharsight Corp., Palo Alto, CA, USA).
`tionship to study drug was determined.
`The areas under the concentration versus time
`curves from time zero to infinity (AUC∞) were
`Venous blood samples (10mL) were obtained
`calculated using a combination of the linear and
`from an indwelling catheter at 0 (predose), 5, 10, 15,
`logarithmic trapezoidal rules, with extrapolation to
`20, 30 and 45 minutes, and 1, 2, 3, 4, 6, 8, 12 and 16
`infinity by dividing the last measurable serum con-
`hours after hydromorphone administration. The
`centration by the elimination rate constant (λz).[12]
`samples were collected in Vacutainer® tubes con-
`taining the anticoagulant sodium heparin, cen- Values for maximum concentration (Cmax) and time
`trifuged at 4°C to separate the plasma and the cells,
`to Cmax (tmax) were determined by WinNonlin. The
`
`Assay of Samples
`
`The sample analysis was conducted using a liq-
`uid chromatography/mass spectrometry/mass spec-
`troscopy assay method by AAI International, Inc. –
`Kansas City (Shawnee, KS, USA). Concentrations
`<20 ng/L were reported as below the quantitation
`limit. Samples with concentrations >2000 ng/L were
`reanalysed using a dilution so that the assayed con-
`centration was within the range of 20–2000 ng/L.
`Between-day and within-day accuracy and precision
`were <12% relative standard deviation.
`
`Pharmacokinetic Analysis
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
`AQUESTIVE EXHIBIT 1120 Page 0003
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`

`

`636
`
`Davis et al.
`
`Table I. Mean (coefficient of variation [CV] %) single-dose hydromorphone pharmacokinetic parameters following administration of intrave-
`nous (IV; treatment A) and intranasal (IN) hydromorphone HCl 2.0mg in patients with untreated (treatment B) or treated (treatment C) rhinitis
`(n = 10; except n = 9 in treatment A due to inadequate characterisation of the elimination rate constant for one of the subjects)
`Pharmacokinetic parameter
`Treatment A
`Treatment B
`Treatment C
`(2.0mg IV)
`(2.0mg IN)
`(2.0mg IN pretreated)
`0.167 (0.133–0.167)
`0.333 (0.250–0.750)
`0.358 (0.167–0.767)
`tmax (h)
`Cmax (µg/L)
`32.48 (29.0)
`3.69 (46.1)
`3.38 (63.3)
`4.77 (42.5)
`6.13 (55.5)
`6.32 (63.4)
`t1/2 (h)
`AUCt (µg • h/L)
`13.7 (18.3)
`8.41 (35.3)
`7.61 (48.9)
`AUC∞ (µg • h/L)
`14.1 (20.7)
`9.19 (37.2)
`8.43 (47.0)
`2.90 (31.8)
`5.47 (34.7)
`6.13 (47.4)
`MRT (h)
`131 (24.0)
`212 (28.3)
`252 (40.1)
`CL or CL/F (L/h)
`367 (24.7)
`Vss (L)
`54.4 (34.8)
`59.8 (22.1)
`Assume 100
`F (%)
`AUC∞ = area under the plasma concentration-time curve from time zero to infinity; AUCt = area under the plasma concentration-time curve
`from time zero to last time point; CL = clearance; CL/F = clearance/bioavailability; Cmax = maximum plasma concentration; F =
`bioavailability; MRT = mean residence time; tmax = time to maximum plasma concentration; t1/2 = elimination half-life; Vss = steady-state
`volume of distribution.
`
`elimination half-life (t1/2) was determined from
`0.693/λz. Clearance/bioavailability (CL/F) was cal-
`culated by dividing the dose by AUC∞. Volume of
`distribution at steady state (Vss) was determined by
`moment curves. Vss was calculated as CL • MRT for
`IV data with the correction for the infusion time,
`where MRT is mean residence time.[13]
`
`Statistical Considerations
`
`Statistical analyses were performed with PC-
`SAS (version 6.12, SAS Institute, Cary, NC, USA).
`The statistical tests were 2-sided with a critical level
`of 0.05. An analysis of variance (ANOVA) with
`factors and subject sequence, treatment and period
`was performed for log-transformed AUC and Cmax.
`The
`least-square geometric means
`from
`the
`ANOVA were used to calculate the ratios and their
`90% confidence intervals (CIs) between treatment
`groups for AUC and Cmax. The carryover effect for
`the two intranasal treatments was analysed using an
`ANOVA of log-transformed AUC and Cmax. Rank-
`transformed PK parameters (F and tmax) were
`analysed using an ANOVA with effects for se-
`quence, subject (sequence), treatment and period.
`
`Results
`
`Safety Assessment
`
`All 12 patients who enrolled in the study were
`Caucasian. Ten patients completed the study with-
`out clinically significant or serious adverse events.
`Two subjects dropped out for reasons unrelated to
`the study drug. There were no clinically relevant
`changes in physical examination, nasal evaluations
`or laboratory tests. The adverse effects, as reflected
`by number and intensity of adverse response, were
`greater for the IV treatment compared with the two
`intranasal treatments. The most common side effects
`were associated with known hydromorphone effects
`(i.e. dizziness, sedation, nausea, etc.). A frequently
`reported adverse effect for the IN formulation was a
`“bad (or bitter) taste in the back of the throat”, but it
`resolved in 20–60 minutes.
`
`Pharmacokinetics and Statistical Analyses
`
`Table I summarises pharmacokinetic data for the
`three treatments. Median tmax values were 20 and
`21.5 minutes for the intranasal doses after treatment
`B (no pretreatment) and treatment C (decongestant
`pretreatment), respectively, suggesting similar ab-
`sorption rates in the two treatment groups. The
`differences in tmax and F between treatments B and
`C were not statistically significant (p > 0.8 and
`> 0.4, respectively). The area under the plasma con-
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
`AQUESTIVE EXHIBIT 1120 Page 0004
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`

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`Pharmacokinetics of Intranasal Hydromorphone
`
`637
`
`Discussion
`
`centration-time curve from time zero to the last time
`point (AUCt) and AUC∞ were comparable between
`Plasma concentrations and pharmacokinetic
`the two IN treatments as shown by treatments C/B
`parameters of hydromorphone in patients with rhini-
`ratios (90% CIs) of 0.89 (0.75, 1.04) and 0.90 (0.77,
`tis were found to be very similar to healthy volun-
`1.04), respectively. Treatments C/B ratios (90% CI)
`teers.[14] The IN formulation of hydromorphone had
`rapid absorption (median peak times of 20 and 21.5
`for Cmax were 0.83 (0.61, 1.14).
`minutes after treatments B and C, respectively).
`Of the ten subjects who completed the study, four However, one subject (who received oral pseudo-
`received nasal oxymetolazone and six received oral
`ephedrine in treatment C) had much higher concen-
`pseudoephedrine as pretreatment for rhinitis. How-
`trations than average after each treatment that signif-
`icantly contributed to the reported tmax and Cmax
`ever, the data obtained in treatment C were limited
`values. The data from this subject also contributed to
`by sample size and did not allow for a statistical
`a noticeable difference following treatment B be-
`comparison between pretreatments.
`tween median tmax (21.5 minutes) and the time to
`Statistical analysis of carryover effect on log
`reach the average peak concentration (10 minutes)
`as shown in the concentration-time plot (figure 1
`transformed AUC∞, AUCt and Cmax for the two
`inset). Cmax, AUC, CL, Vss and t1/2 and MRT values
`IN treatments was performed. p-Values from an
`after the IV dose were very similar to other stud-
`ANOVA with factors sequence, subject (sequence),
`ies.[5,7,8] Mean absolute bioavailability for the 2.0mg
`treatment and period for sequence BC and CB were
`IN dose in healthy volunteers was 57% (range
`>0.13, so the carryover effects were not significant.
`36–78%). The range of bioavailability values in this
`
`IV
`IN
`IN pretreatment
`
`0
`
`1
`
`2
`
`3
`
`0123456
`
`50
`
`10
`
`1
`
`0.1
`
`Plasma concentration (µg/L)
`
`0.05
`
`0
`
`2
`
`4
`
`6
`Time (h)
`Fig. 1. Mean (n = 10) plasma hydromorphone concentration vs time profiles following a single dose of hydromorphone hydrochloride (HCl)
`2.0mg by intravenous (IV) infusion (treatment A) and intranasal (IN) hydromorphone HCl 2.0mg without (treatment B) and with (treatment C)
`pretreatment with decongestants. The inset figure shows a comparison of treatments B and C during the first 3 hours.
`
`8
`
`10
`
`12
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
`AQUESTIVE EXHIBIT 1120 Page 0005
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`

`

`638
`
`Davis et al.
`
`study was more variable (33–96%), but the mean with decongestants did not significantly alter the
`absolute bioavailability values were similar to
`rate of absorption in rhinitis patients as measured by
`healthy volunteers (54.4–59.8%). The large varia-
`tmax. For comparison, the median tmax was 25 min-
`tion, small numbers of subjects in this study, and
`utes for the 2.0mg IN dose in healthy subjects. These
`lack of direct comparison in this study preclude
`findings suggest that pretreatment with oral or IN
`definitive conclusions regarding significance of dif-
`decongestants do not significantly affect bioavaila-
`ferences between healthy subjects and patients with
`bility of hydromorphone in rhinitis. However, since
`rhinitis.
`different pretreatments and routes of administration
`were used in treatment C, any conclusions about the
`The concentrations observed in this study are
`effects of individual rhinitis pretreatments on the
`within the reported therapeutic range when adjusted
`disposition of intranasal hydromorphone are limit-
`by dose. Reidenberg et al.[15] measured hydromor-
`ed.
`phone concentrations in serum samples from pa-
`tients treated for chronic severe pain and estimated
`the minimum effective plasma concentration at ap-
`proximately 4 µg/L. Inturrisi et al.[16] demonstrated
`for patients with chronic pain with cancer a half-
`maximal concentration of 20 µg/L was required to
`maintain a therapeutic effect. However, both of
`these studies demonstrated wide interindividual
`variability with the reported concentrations.
`The present study demonstrated that inflamma-
`tion of the nasal mucosa did not significantly affect
`the rate and extent of absorption of IN hydromor-
`phone. These data are consistent with those observ-
`ed with other drugs including butorphanol,[17] buser-
`elin[18] and triamcinolone.[19] However, bioavailabil-
`ity of desmopressin apparently increased in healthy
`males after experimental induction of rhinitis.[20]
`The increase in intranasal desmopressin absorption
`was attributed to increased blood flow.
`Shyu et al.[17] found that pretreatment with ox-
`ymetazoline did not affect the bioavailability of IN
`butorphanol in rhinitis patients. Absolute bioavaila-
`bility of IN butorphanol was 69% and 72% when
`administered with and without oxymetazoline, re-
`spectively. Cmax values were significantly lower and
`mean absorption times of IN butorphanol were sig-
`nificantly greater in the oxymetazoline-treated pa-
`tients, suggesting that vasoconstriction and reduced
`blood flow did affect the rate of butorphanol absorp-
`tion. However, based on similar AUCs, the authors
`concluded that butorphanol doses should not be
`adjusted in rhinitis patients when they are pretreated
`with oxymetazoline.
`Comparison of treatments B and C showed there
`was not a significant difference in the extent of
`absorption of hydromorphone in pretreated and un-
`treated nonallergic rhinitis subjects. Pretreatment
`
`Acknowledgements
`
`This study was financially supported by Intranasal Tech-
`nology, Inc., Lexington, KY, USA. Dr Rudy is currently
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
`AQUESTIVE EXHIBIT 1120 Page 0006
`
`Bioavailability of IN hydromorphone has been
`investigated in animal models. Chang et al.[21] ad-
`ministered a 5 mg/kg dose of hydromorphone by IV
`and IN routes to three New Zealand male rabbits,
`which have an olfactory mucosa with a large surface
`area that is comparable to humans. The systemic
`bioavailability of IN hydromorphone was 103.62 ±
`4.79%, much higher than in the present study. The
`finding of greater bioavailability compared with the
`current study is most likely due to the fact that the
`study by Chang et al. used an in situ nasal recircula-
`tion method to evaluate the nasal absorption and
`there was much greater opportunity for hydromor-
`phone absorption.
`
`Conclusions
`
`Pretreatment of vasomotor rhinitis with oral or
`IN decongestants did not significantly affect the rate
`or extent of absorption of hydromorphone in this
`study. There was not a significant difference in
`bioavailability between treated and untreated rhini-
`tis. There were no clinically relevant changes in
`physical examination, nasal evaluations or labora-
`tory tests. In general, the adverse events observed
`were those commonly associated with hydromor-
`phone, namely sedation and nausea. The alternative
`delivery system of IN hydromorphone achieved
`therapeutic concentrations and demonstrated a fa-
`vourable pharmacokinetic profile that may provide a
`convenient, noninvasive route for a rapidly acting
`opiate analgesic for treating acute pain.
`
`

`

`Pharmacokinetics of Intranasal Hydromorphone
`
`639
`
`employed by Intranasal Technology, Inc. Drs Wermeling and
`Archer are paid consultants to Intranasal Technology, Inc.
`
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`
`Correspondence and offprints: Dr Anita C. Rudy, Intranasal
`Technology, Inc., 1513 Bull Lea Boulevard, Lexington, KY
`40511-1200, USA.
`E-mail: arudy@intranasal.com
`
`© 2004 Adis Data Information BV. All rights reserved.
`
`Clin Drug Invest 2004; 24 (11)
`
`AQUESTIVE EXHIBIT 1120 Page 0007
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